key: cord-0944924-w4my1i2g
authors: Zhang, Mengmeng; Chen, Luni; Qian, Jiaming
title: Gastrointestinal Manifestations and Possible Mechanisms of COVID‐19 in Different Periods
date: 2021-11-05
journal: J Dig Dis
DOI: 10.1111/1751-2980.13065
sha: aa1167b6b9334842b228968db034cd228f397724
doc_id: 944924
cord_uid: w4my1i2g

Coronavirus disease 2019 (COVID‐19), as a new infectious disease, has spread worldwide. COVID‐19 mainly impacts respiratory system, but digestive manifestations have been frequently described in COVID‐19 cases as well, even as the initial symptoms. And there have been several reports about the different gastrointestinal (GI) manifestations in mild and severe patients or in remission stages. So it is reasonable to consult that GI symptoms have distinct characteristics in different periods of COVID‐19. Therefore, this review article will try to summarize the gastrointestinal manifestations and possible mechanisms of COVID‐19 in different periods, and explain the significance of gastrointestinal manifestations in systemic inflammatory injury. This article is protected by copyright. All rights reserved.

and is also reasonable to be regarded as an indication of poor prognosis due to increased secondary infective risks and multisystem involvement 14, 15, 22, 23 . Besides these, almost half of the patients with COVID-19 have taste disorders as a coexistent or the only clinical manifestation 24, 25 . The possible mechanism is mainly associated with angiotensin converting enzyme 2 (ACE2), one of SARS-CoV-2 binding receptors. Besides the certain distribution in pulmonary alveolar cells, ACE2 also widely exist in GI epithelial cells including oral mucosa 26, 27 . The Spike protein on the surface of SARS-CoV-2 may directly damage GI epithelial cells by binding to ACE2, and it turns out the loss of the normal function of ACE2, which results in the disturbed intestinal amino acid metabolism and microecological imbalance, and eventually induces intestinal inflammation and immune disorders 23, 28 .

Abdominal pain is relatively rare, but more importantly, it always requires to be differentiated from several acute abdomen conditions cautiously, which are more common in clinical work, especially not accompanied by other manifestations except for GI symptoms. There were many case reports in adults or children [29] [30] [31] who suffered from different degrees of abdominal pain at the beginning of the illness, which can be diffuse or limited to the right lower abdomen or around the umbilicus with diarrhea and vomiting or not, and some had abdominal tenderness and muscle tension. Their abdominal computerized tomography (CT) scan showed no manifestations of peritonitis or appendicitis. The detection of nucleic acid of SARS-CoV-2 through real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was sometimes negative, not parallel to their clinical manifestations, which makes the confirmation of COVID-19 more difficult and needs to detect SARS-CoV-2 many times later or make diagnosis until the occurrence of respiratory symptoms and changes of chest CT scan 18, 32 .

It is noteworthy that viral infections usually have a prodrome of non-specific GI symptoms, which makes the diagnosis of GI involvement in COVID-19 cases more challenging in the early stage. However, from the perspective of its acute and severe onset, it is the mild prodrome that leads to scarce attention to COVID-19 and treatment delay 33 . In this condition, epidemiological investigation needs to be considered. For suspected cases, it is essential and urgent to complete SARS-CoV-2 and radiologic detection to determine COVID-19. Then, fecal test for SARS-CoV-2 is also a convenient option to help differentiate prodrome and GI involvement. In terms of duration and severity, prodromal symptoms tend to be transient and self-limiting, while for COVID-19 cases, GI symptoms persisted around 10 days mostly and had a possibility of aggravation with respiratory deterioration. Moreover, other factors should not be neglected, such as prior or current drug usage, history of GI comorbidities. The microbial agents may have effects on the gut immune response, gut microbiota, and in turn the clearance of virus from the gut, which can play a role in combination in the GI symptoms in COVID-19 patients 34 . Therefore, American Gastroenterological Association (AGA) Institute suggests that for COVID-19 patients undergoing medications, treatment-related Gl adverse effects should be considered and evaluated 35 .

The appearance and aggravation of GI symptoms can be regarded as one of the criteria of disease progression. The proportion of severe and critically ill patients with GI symptoms was significantly higher than that of mild patients, which predicts the increasing risk of adverse outcomes in COVID-19 patients with GI symptoms (OR=1.9, P=0.047) 3, 19 . In the progression stage, in addition to common non-specific GI symptoms, it mainly causes a variety of GI-related complications, including digestive and absorption dysfunction, GI motility disorder, acute intestinal ischemia, GI bleeding, Clostridium difficile infection (CDI), and pancreatic injury etc..

The dysfunction of digestion and absorption, mainly manifested as intolerance of enteral nutrition (EN), worsening diarrhea, results in lack of nutrients and malnutrition, leading to deterioration of the overall condition. Nutrition plays a vital role in the recovery process of COVID-19 patients. It is suggested that the monitoring of stool weight can be used as a feasible method to assess the nutritional status of severe patients and an indicator for the evaluation of tolerance to EN 36 .

Present findings have shown that half of critically ill patients have severe GI motility disorders 37 . Gastric retention was a common condition as EN was usually given to severe patients through a nasogastric tube. And some patients had typical manifestations of intestinal obstruction, even developing into intestinal necrosis in severe or critical cases which requires emergency surgical treatment. The reason of local or widespread ischemia may be associated with several factors including small intestinal vascular thrombosis, enteric nerve dysfunction caused by viral infection and systemic metabolic and acid-base imbalance 38 .

Many cases reported that COVID-19 patients may have acute abdominal pain, bloody stool, which are in accordance with the features of ischemic bowel disease. Bhayana et al. 39 confirmed the existence of non-occlusive mesenteric ischemia in abdominal CT scan of COVID-19 patients. And pathological evidence was also obtained when the necrotic bowel had to surgically removed for some patients 40, 41 . COVID-19-related hypercoagulability status is now basically validated and always means a poor prognosis 42, 43 . On the basis of the hypercoagulable tendency, coupled with the induction of systemic inflammatory response and cytokine storm, the disease progression is often difficult to control and cause death inevitably.

GI bleeding can also occurred in a few COVID-19 patients with a prevalence of 3.04% approximately 44, 45 . The common reasons includes peptic ulcer, esophagitis, rectal ulcer from rectal tubes 46 . The possible mechanisms include GI mucosal damage caused by virus invasion or long-term hypoxemia or multiple organ failure with coagulation disorders. In addition, there are also drug-related factors, including glucocorticoids and oral nonsteroidal antiinflammatory drugs or anticoagulants due to comorbidities 47 .

The destruction of the intestinal mucosal barrier by SARS-CoV-2 increases the risk of co-infection with other pathogens. There are few reports of positive bacterial cultures in the stool of COVID-19 patients, but most hospitals use antibiotics empirically to reduce the possibility of intestinal-derived bacteremia. However, due to the widespread use of antibiotics, the incidence of CDI is also gradually increasing. Data from the Detroit Medical Center in the United States 22 showed that from March to April 2020, the incidence of CDI increased to 3.6/10,000 patient days, a little more than that in January and February. CDI can appear at the same time as respiratory symptoms, or within 1 week after the diagnosis of COVID-19. Patients with CDI are more severely ill and have a higher mortality rate. Similarly, COVID-19 patients can be combined with cytomegalovirus infection, which is speculated to be related to T lymphocytes function and elevated interleukin-6 (IL-6) levels 48, 49 .

Pancreatic involvement has been reported in some COVID-19 patients including pancreatic enzyme changes, acute pancreatitis and subsequent metabolic disorders [50] [51] [52] . Goyal H et al. 53 found that 11.7% of COVID-19 patients presented with hyperlipasemia ranging from an upper limit around 50-60 U/L to a higher lipase levels over 300 U/L. Unlike the apparent pancreatic impairment in acute pancreatitis, hyperlipasemia in patients with COVID-19 may be occult and unobvious. However, hyperlipasemia may worth more in recognition of disease progression in early period and serum lipase was also suggested as a marker of disease severity in COVID-19 patients. More higher serum lipase levels usually predicted pancreatic damage and have significant association with increased need for ICU admission 54, 55 . The potential mechanisms may include the high ACE2 expression in pancreas, which suggests SARS-CoV-2 can also attack pancreas, leading to direct pancreatic injuries and inflammatory response 53, 56 . Additionally, secondary damage from systematic cytokine storm and drug-related pancreatic injury may be involved 57, 58 .

Additionally, other common GI complications in patients with COVID-19 have been rarely reported until now, such as bowel obstruction or perforation. Similarly, possible causes may be related to direct bowel damage by the SARS-CoV-2 infection, local ischemia or necrosis due to inflammatory response and hypercoagulable state 59, 60 .

Compared with conventional severe patients, critically ill patients with COVID-19 are at increased risk of serious complications as mentioned above 61 and GI dysfunction is closely related to poor prognosis 62, 63 . The potential mechanism mainly involves virus direct invasion through ACE2 and the aggravation of systemic inflammation. As discussed above, digestive system is involved most likely due to the presence of ACE2 in the GI tract, and moreover, Patel SK et al. 64 revealed that plasma ACE2 activity is elevated in patients after COVID-19 infection and is associated with more severe form. In the progressive stage, GI damage caused by lung injury and systematic inflammation play a dominant role. The presence of "gut-lung axis" further impaired pulmonary and GI functions through microbial metabolites and abnormal immune response. Lung-derived abnormal cytokines and T cells elevated after viral infection, which promoted interaction with receptors in GI tract and activated more intense response in the gut, leading to intestinal immune damage and disturbance of the intestinal flora 65 . In return, bacterial imbalance and inflammatory molecules from the gut can counteract the lung through bloodstream, further aggravating the lung inflammation 66, 67 . Several studies have revealed that inflammatory indicators generally started to rise from 1-2 weeks after onset of disease, and gradually increased along with the disease progresses 68, 69 . And patients with diarrhea had much higher levels of IL-6, IL-10 and tumor necrosis factor α in the peripheral blood 69 .

The main therapeutic interventions are symptomatic support, non-specific antiviral therapy, and antiinflammatory therapy. Non-specific GI symptoms in mild and common type patients, such as diarrhea and abdominal pain, are self-limited 5, 19 . In the remission stage, symptoms and inflammatory indicators can gradually improve within a few days, but the detection of virus real-time RT-PCR turns negative later than the symptoms disappear, up to about 1 month, and the fecal nucleic acid detection of SARS-CoV-2 may recovers slower than that of nasopharyngeal swab, perhaps owing to the aggregation and colonization of the virus in the GI tract 30, 70 . For severe and critically ill patients, it also includes early start of enteric nutrition, application of glucocorticoids, human gamma globulin, etc 71, 72 . Recent evidence suggests that glucocorticoids can reduce IL-6 levels by activating ACE2 and counteract the systemic inflammatory response to improve lung injury in severe COVID-19 patients 73, 74 , however it requires further validation about whether glucocorticoids can improve GI functions. Other therapies such as interferon or lopinavir/ritonavir, antibacterial drugs, and intestinal microecological modulators have been widely used in clinical practice, but they lack rigorous large-scale clinical trials to validate 75 . The specific antibodies are not produced after recovery from COVID-19. After 4 weeks of discharge, 15.4% of patients were negative for SARS-CoV-2 antibody IgG and IgM, and some cases of re-infection were also reported 76 .

Regarding COVID-19 cases with pre-existing chronic GI disorders, cancer and inflammatory bowel disease (IBD) were the most commonly studied. Several studies indicated that patients with gastrointestinal malignancies were more susceptible to COVID-19 and had more possibility to manifest in a severe form, which perhaps resulted from higher expression ACE2 and TMPRSS2 77, 78 . And for IBD patients, they seemed not to have an increased risk for COVID-19. But medications for IBD may affected COVID-19 course. Treatment with 5-aminosalicylates had higher COVID-19 mortality 79 and anti-TNF therapy may attenuated serological responses to SARS-CoV-2 vaccination 80 .

Endoscopic assessment is generally performed for diagnostic and therapeutic purposes in patients with digestive symptoms. But in the COVID-19 pandemic, upper endoscopy or colonoscopy were restricted and delayed mainly because of its excess burden of respiratory function or increasing risk for viral transmission during endoscopic procedures 81 . For breaking out of this dilemma, endoscopic necessity should be fully evaluated and risk stratification of GI disease and COVID-19 should be consulted 82, 83 . For example, it is inevitable for patients with acute or recurrent persistent GI bleeding to receive endoscopic procedures. Under this condition, intra-or post-procedure risk management should be further implemented as the statement from European Society of Gastrointestinal Endoscopy and the European Society of Gastroenterology and Endoscopy Nurses and Associates 82 . Moreover, some invasive procedures can be considered as a safe and adequate alterative for disease screening to minimize patient and personnel unnecessary exposure to SARS-CoV-2, such as fecal and radiologic tests or capsule endoscopy 84, 85 .

The GI manifestations can be applied as an auxiliary index to assess the disease severity and predict the outcome of disease, combined with other vital signs and supplementary examinations. There are also some limitations about the GI features and COVID-19 we should realize. There are no strict standards and it is hard to distinguish the specific stage of GI manifestations sometimes because of the distinct individual conditions and the overlapping nature of symptoms. But we think it is quite valuable to provide some clues for the overall judgement for COVID-19 severity by different GI symptoms. And the combination of GI manifestations with pulmonary or systematic conditions is extremely essential. Besides, as the lack of specificity, many potential factors require to be summarized as well, such as digestive comorbidities, medications, mental states, and functional GI diseases. And the long-term impacts of COVID-19 on the GI tract need to be followed up. Further studies are demanded to thoroughly identify the role of GI manifestations in the pathogenesis or progression of COVID-19 and provide more potential treatment for entire rehabilitation for COVID-19 patients in this worldwide disaster.

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The authors have no conflict of interest.

The data underlying this study are available from corresponding author upon reasonable request.